Interrogating the bioactive pharmacophore of the latrunculin chemotype by investigating the metabolites of two taxonomically unrelated sponges.
This study involved a campaign to isolate and study additional latrunculin analogues from two taxonomically unrelated sponges, Cacospongia mycofijiensis and Negombata magnifica. A total of 13 latrunculin analogues were obtained by four different ways, reisolation (1-4), our repository (5, 6), new derivatives (7-12), and a synthetic analogue (7a). The structures of the new metabolites were elucidated on the basis of a combination of comprehensive 1D and 2D NMR analysis, application of DFT calculations, and the preparation of acetonide derivative 7a. The cytotoxicities against both murine and human cancer cell lines observed for 1, 2, 7, 7a, 8, 9, and 12 were significant, and the IC(50) range was 0.5-10 microM. Among the cytotoxic derivatives, compound 9 did not exhibit microfilament-disrupting activity at 5 microM. The implications of this observation and the value of further therapeutic study on key latrunculin derivatives are discussed.
Amagata
Taro
T
Department of Chemistry and Biochemistry and Department of Ocean Sciences, University of California Santa Cruz, Santa Cruz, California 95064, USA.
Johnson
Tyler A
TA
Cichewicz
Robert H
RH
Tenney
Karen
K
Mooberry
Susan L
SL
Media
Joseph
J
Edelstein
Matthew
M
Valeriote
Frederick A
FA
Crews
Phillip
P
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008956:Models, Chemical; D008968:Molecular Conformation; D011161:Porifera / Q000737:chemistry / Q000145:classification* / Q000378:metabolism*; D013237:Stereoisomerism; D053778:Thiazolidines / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D006574:Heterocyclic Compounds, 2-Ring; D007783:Lactones; D053778:Thiazolidines; C037068:latrunculin B; C037067:latrunculin A